General Principles And Choice Of Drugs For The Therapy Of The Epilepsies

Early diagnosis and treatment of seizure disorders with a single appropriate agent offers the best prospect of achieving prolonged seizure-free periods with the lowest risk of toxicity (see Table 19-1). A balancing of efficacy and unwanted effects in the individual patient provides the optimal therapeutic choice.

The first consideration is whether to initiate treatment. For example, drug therapy may not be necessary after an isolated tonic-clonic seizure in a healthy young adult who lacks a family history of epilepsy and who has a normal neurological exam, EEG, and brain magnetic resonance imaging (MRI) scan—a setting where the risk of a drug reaction approximates the likelihood of seizure recurrence in the next year (15%). Alternatively, a similar seizure occurring in an individual with a positive family history of epilepsy, an abnormal neurological exam, an abnormal EEG, and an abnormal MRI carries a recurrence risk of 60% that favors initiation of therapy.

Unless extenuating circumstances exist (e.g., status epilepticus), therapy should be initiated with a single drug, typically in dosage expected to provide a plasma concentration in the lower portion of the therapeutic range. To minimize dose-related adverse effects, therapy may be initiated at reduced dosage, increasing dosage at appropriate intervals, as required for control of seizures or as limited by toxicity, preferably assisted by monitoring of plasma drug concentrations.

Faulty compliance is the most frequent cause for failure of therapy with antiseizure drugs; regularity of medication is essential. Compliance with a properly selected, single drug in maximal tolerated dosage results in complete control of seizures in -50% of patients. If a seizure occurs despite therapeutic drug levels, the physician should assess the presence of potential precipitating factor (e.g., sleep deprivation, concurrent febrile illness, or drugs, including caffeine or over-the-counter medications). If compliance is confirmed yet seizures persist, another drug should be substituted. Unless serious adverse effects of the drug dictate otherwise, dosage always should be reduced gradually when a drug is discontinued to minimize risk of seizure recurrence. In the case of partial seizures in adults, the diversity of available drugs permits selection of a second drug that acts by a distinct mechanism.

In the event that therapy with a second single drug also is inadequate, many physicians resort to treatment with two drugs simultaneously. This decision should not be taken lightly, because most patients obtain optimal seizure control with fewest unwanted effects when taking a single drug. Nonetheless, some patients will not be controlled adequately without the simultaneous use of two or more antiseizure drugs. No properly controlled studies have systematically compared one particular drug combination with another, and the chances of complete control with this approach are not high. It seems wise to select two drugs that act by distinct mechanisms (e.g., one that promotes Na+ channel inactivation, another that enhances GABA-mediated synaptic inhibition). Additional issues are the unwanted effects of each drug and the potential drug interactions. Many of these drugs induce expression of CYPs and thereby alter the metabolism of themselves and/or other drugs (see Table 19-2).

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